Phenoxyimino carboxylic acids and esters

ABSTRACT

Tricyclic compounds of the formula   WHEREIN R1 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, cyano, carbamoyl, carboxy, lower alkoxy carbonyl, nitro, amino, mono-lower alkylamino, dilower alkylamino, acyl, acylamido, sulfamoyl, di-lower alkylsulfamoyl, or difluoromethylsulfonyl; R2 is hydrogen, lower alkyl, amino-lower alkyl, mono-lower alkyl-amino-lower alkyl, or di-lower alkylamino-lower alkyl; n and r are independently 1 or 2; and X is oxygen or sulfur, PREPARED, INTER ALIA, FROM THE CORRESPONDINGLY SUBSTITUTED PHENOL OR THIOPHENOL AND HALOKETOCYCLOHEXANE OR PENTANE CARBOXYLIC ACID ESTER, ARE DESCRIBED. The end products are useful as anti-inflammatory and anti-rheumatic agents.

United States. Patent Berger et al.

[ Apr. 1,1975

PHENOXYIMINO CARBOXYLIC ACIDS AND ESTERS lnventors: Leo Berger, 7 TheParkway; Willy Leimgruber, 166 Highland Ave., both of Montclaire, N..l.;Fausto Eugenio Schenker, 45 lm Hirshalm, Riehen, Switzerland Filed: Nov.23, 1973 Appl. No.: 418,714

Related U.S. Application Data Division of Ser. No. 234,375, March 13,1972, which is a continuation-in-part of Ser. No. 128,570, March 26,1971, abandoned.

U.S. Cl...... 260/518 R, 260/471 A, 260/471 R, 260/518 A Int. Cl. C07c101/36 Field of Search 260/471 A, 471 R, 518 R, 260/518 A ReferencesCited UNITED STATES PATENTS 5/1974 Hubcle 260/471 R PrimaryExaminer-Lorraine A. Weinberger Assistant Examiner-L. A. ThaxtonAttorney, Agent, or Firm-Samuel L. Welt; Bernard S. Leon; William G.lsgro [57] ABSTRACT Tricyclic compounds of the formula 1 coona wherein Ris hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio,trifluoromethyl, cyano, carbamoyl, carboxy, lower alkoxy carbonyl,nitro, amino, mono-lower alkylamino, di-lower alkylamino, acyl,acylamido, sulfamoyl, di-lower alkylsulfamoyl, ordifluoromethylsulfonyl; R is hydrogen, lower alkyl, amino-lower alkyl,mono-lower alkyl-amino-lower alkyl, or di-lower alkylamino-lower alkyl;11 and r are independently 1 or 2; and X is oxygen or sulfur, prepared,inter alia, from the correspondingly substituted phenol 0r thi'ophenoland haloketocyclohexane or pentane carboxylic acid ester, are described.The end products are useful as antiinflammatory and antirh eumaticagents.

3 Claiins, No Drawings BRIEF SUMMARY OF THE INVENTION The inventionrelates to racemic compounds of the formula COORa wherein Rindependently, is hydrogen, halogen, lower alkyl, lower alkoxy, loweralkylthio, trifluoromethyl, cyano, carbamoyl, carboxy, lower alkoxycarbonyl, nitro, amino, mono-lower alkylamino, di-lower alkylamino,acyl, acylamido, sulfamoyl, di-lower alkylsulfamoyl, ordifluoromethylsulfonyl; R is hydrogen, lower alkyl, amino-lower alkyl,mono-lower alkylamino-lower alkyl or di-lower alkylamino-lower alkyl; nand r are independently l or 2; and X is oxygen or sulfur, theirenantiomers, and when R is carboxy and/or R is hydrogen, salts thereofwith pharmaceutically acceptable bases, and when R is amino, mono-loweralkylamino or di-lower alkylamino, and/or when R is amino-lower alkyl,mono-lower alkylamino-lower alkyl, or di-lower alkylamino-lower alkyl,addition salts thereof with pharmaceutically acceptable acids.

The compounds of formula I are useful as antiinflammatory andanti-rheumatic agents.

In other aspects, the invention relates to intermediates of the formulaswherein R R R R r, n and X are as herein described.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term loweralkyl denotes a straight or branched chain hydrocarbon group containing1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tertiary butyl, neopentyl, pentyl, heptyl, and the like. Theterm lower alkoxy denotes an alkyl ether group in which the alkyl groupis as described above, for example, methoxy, ethoxy, propoxy,isopropoxy, butoxy, pentoxy and the like. The term lower alkylthiodenotes an alk'ylthio ether group in which the alkyl group is asdescribed above, for example, methylthio, ethylthio, propylthio,isopropylthio, butylthio, pentyl'thio, and the like. The term halogendenotes all the halogens; that is, bromine, chlorine, fluorine andiodine; bromine and chlorine are preferred. The term acyl denotes analkanoyl group derived from an aliphatic carboxylic acid of 1 to 7carbon atoms, for example, formyl, acetyl, propionyl, and the like, andan aroyl group derived from an aromatic carboxylic acid, such as benzoyland the like. Exemplary of acylamido are acetamido, benzylamido and thelike. Exemplary of mono-lower alkylamino are methylamino, ethylamino andthe like. Exemplary of dilower alkylamino are dimethylamino,diethylamino and the like. Exemplary of amino-lower alkyl areaminomethyl, aminoethyl and the like. Exemplary of monoloweralkylamino-lower alkyl are methylaminomethyl, ethylaminoethyl and thelike. Exemplary of di-lower alkylamino-lower alkyl aredimethylaminomethyl, diethylaminoethyl and the like. Exemplary ofdi-lower alkylsulfamoyl are dimethylsulfamoyl, diethylsulfamoyl and thelike. The invention relates to racemic compounds of the formula COO 2wherein R, is hydrogen, halogen, lower alkyl, lower alkoxy, loweralkylthio, trifluoromethyl, cyano, carbamoyl, carboxy, loweralkoxycarbonyl, nitro, amino, mono-lower alkylamino, di-loweralkylamino, acyl, acylamido, sulfamoyl, di-lower alkylsulfamoyl ordifluoromethylsulfonyl; R is hydrogen, lower alkyl, amino-lower alkyl,mono-lower alkylamino-lower alkyl or di-lower alkylaminolower alkyl; nand r are independently 1 or 2; and X is oxygen, sulfur, theirenantiomers, and when R is carboxy and/or R is hydrogen, salts thereofwith pharmaceutically acceptable bases, and when R is amino, mono-loweralkylamino or di-lower alkylamino, and/or when R, is amino-lower alkyl,mono-lower alkylamino-lower alkyl, or di-lower alkylamino-lower alkyl,addition salts thereof with pharmaceutically acceptable acids.

A preferred sub-genus of the invention comprises racemic compounds ofthe formula 11),. I cooR Ia (R1) Ib COO X wherein R R r and X are aspreviously described,

their enantiomers, and the respective salts thereof as herein described.Preferred compounds of formula Ib are those wherein X is oxygen.

Preferably, in formulas I, la and lb, R, is hydrogen, halogen, loweralkyl, lower alkoxy, cyano, carboxy, lower alkoxycarbonyl, nitro, amino,mono-lower alkylamino, di-lower alkylamino, acyl or acylamido; and R ishydrogen or lower alkyl.

The preferred compounds of the invention comprise compounds of theformula R1 COORZ wherein R is as previously described, and R isindependently hydrogen, chlorine or cyano, provided that at least one ofR is hydrogen,

their enantiomers and the respective salts thereofas herein described.

The most preferred compounds of the invention are:

8-chlorol ,2-dihydro-3 4H )-dibenzofurancarboxylic acid;

7-chlorol ,2-dihydro-3 4H)-dibenzofurancarboxylid acid; and

8 -cyanol ,2-dihydro-3 4H )-dibenzofurancarboxylic acid.

Exemplary of the compounds of the invention corresponding to formula Iwherein n is 2 and X is oxygen are:

' l,2-dihydro-3(4H),8-dibenzofurandicarboxylic acid; 8-acetyll,2-dihydro-3(4H)-dibenzofuran carboxylic acid;

8-amino-l ,2-dihydro-3(4H)-dibenzofuran carboxylic acid;

8-aminol ,2-dihydro-3(4HH)-dibenzofuran carboxylic acid ethyl ester;

7-aminol ,2-dihydro-3(4H)-dibenzofuran carboxylic acid ethyl ester;

7-aminol ,2-dihydro-3 (4H )-dibenzofuran carboxylic acid;

8-chloro- 1 ,2-dihydro-3 4H )-dibenzofuran carboxylic acid;

6-chloro- 1 ,2-dihydro-3 4H )-dibenzofuran carboxylic acid;

9-chloro-l ,2-dihydro-3 4H )-dibenzofuran carboxylic acid methyl ester;

9-chloro-1 ,2-dihydro-3 4H )-dibenzofuran carboxylic acid;

7-chloro-l ,2-dihydro-3 4H )-dibenzofuran carboxylic acid;

l,2-dihydro-8-nitro-3(4H)-dibenzofura.n carboxylic acid;

8-fluoro-l ,2-dihydro-3 4H )-dibenzofuran carboxylic acid;

8-methyl- 1 ,2-dihydro-3 4H )-dibenzofuran ylic acid;

carbox- 7-acetamido-l ,2-dihydro-3 4H )-dibenzofuran carboxylic acidethyl ester;

7-acetamidol ,2-dihydro-3(4H)-dibenzofuran carboxylic acid;

1 ,2-dihydro-7-methoxy-3 (4H)-dibenzofuran carboxylic acid;

7 ,9-dimethoxy- 1 ,2-dihydro-3 4H )-dibenzofuran carboxylic acid;

7,9-dichloro-l ,2-dihydro-3(4H )-dibenzofuran boxylic acid;

8-cyano-l ,2-dihydro-3 (4H )-dibenzofuran carboxylic acid;

8-cyano-3 ,4-dihydrol (2l-I)-dibenzofuran carboxylic acid;

C ar- 8-carbamoyl-l ,2-dihydro-3(4H)-dibenzofuran carboxylic acid ethylester;

8-cyano-3 ,4-dihydro-2( l H)ldibenzofuran carboxylic acid; and the like.

Exemplary of the compounds of the invention corresponding to formula Iwherein n is l and X is oxygen are:

2,3-dihydro-lH-cyclopenta[b]benzofuran-2- carboxylic acid;

7-chloro-2,3-dihydro- 1H-cyclopenta[b]benzofuran- 2-carboxylic acid;

7-acetyl-2,3-dihydro- 1 H-cyclopenta[b ]benzofuran- 2-carboxylic acid;

7-amino-2,3-dihydro- 1 H-cyclopenta[ b] benzofuran- 2-carboxylic acid;

7-amino-2,3-dihydro- 1 H-cyclopenta[ b] benzofuran- 2-carboxylic acidethyl ester;

6-amino-2,3-dihydrol H-cyclopenta[ b] benzofuran- 2-carboxylic acid;

5-chloro-2,3-dihydro-lH-cyclopenta[b]benzofuran- 2-carboxylic acid;

6-chloro-2,3-dihydrol H-cyclopenta[b ]benzofuran- 2-carboxylic acid;

8-chloro-2,3-dihydrol H-cyclopenta[b ]benzofuran- 2-carboxylic acid;

7-nitro-2,3-dihydro- 1 H-cyclopenta[ b]benzofuran-2- carboxylic acid; I

7-fluoro-2,3 -dihydrol H-cyclopenta[ blbenzofuran- 2-carboxylic acid;

7-methyl-2,3-dihydro- 1 H-cyclopenta[b ]benzofuran- Exemplary of thecompounds of the invention corre-- sponding to formulal wherein n is 2and X is sulfur are: 1,2-dihydro-3(4H)-dibenzothiophene carboxylic acid;

8-chlor0- l ,2-dihydro-3(4H )-dibenzothiophene carboxylic acid ethylester;

8-chlorol ,2-dihydro-3(4H )-dibenzothiophene carboxylic acid;

8-acetyl-1,2-dihydro-3(4I-l)-dibenzothiophene carboxylic acid;

8-amino-l,2-dihydro-3(4I-l)-dibenzothiophene carboxylic acid;

8-amino-l,2-dihydr0-3(4H)-dibenzothiophene carboxylic acid ethyl ester;

7-amino-l ,2-dihydro-3 4I-I )-dibenzothiphene carboxylic acid;

7-amino-1 ,2-dihydro-3 (4H )-dibenzothiophene carboxylic acid methylester; 7

8-chloro-1 ,2-dihydro-3 (4H )-dibenzothiophene carboxylic acid;

6-chloro-l ,2-dihydro-3 4H )-dibenzothiophene carboxylic acid;

9-chloro-l ,2-dihydro-3 4H )-dibenzothiophene carboxylic acid;

9-chloro- 1 ,2-dihydro-3(4H)-dibenzothiophene carboxylic acid propylester;

-7-chloro- 1 ,2-dihydro-3(4H)-dibenzothiophene carboxylic acid;

8-nitro-l ,2-dihydro-3(4H)-dibenzothiophene carboxylic acid;

8-fluoro- 1 ,2-dihydro-3 4H )-dibenzothiophene boxylic acid;

8-methyll ,2-dihydro-3(4H)-dibenzothiophene carboxylic acid;

7-acetamido-l ,2-dihydro-3 (4H )-dibenzothiophene carboxylic acid methylester;

7-methoxy-l ,2-dihydro-3(4H)-dibenzothiophene carboxylic acid;

7,9-dimethoxy-l ,2-dihydro-3(4H)-dibenzothiophene carboxylic acid;

7,9-dichloro-l ,2-dihydro-3(4I-I)-dibenzothiophene carboxylic acid;

8-cyanol ,2-dihydro-3(4H)-dibenzothiophene boxylic acid;

8-carbamoyl- 1 ,2-dihydro-3 4H )-dibenzothiophene carboxylic acid, andthe like.

Exemplary of the compounds of the invention corresponding to formula Iwherein n is 1 and X is sulfur are: 2,3-dihydrol H-cyclopenta[b][l]benzothiophene-Z- carboxylic acid;

7-chloro-2,3-dihydro-1H- cyclopenta[ b] [l]benzothiophene-2-carboxylicacid;

7-acetyl-2,3-dihydro-l l-I-cyclopenta[b] [l]-benzothiophene-Z-carboxylic acid;

7-amino-2,3-dihydrol H- cyclopenta[b] [l]benzothiophene-Z-carboxylicacid;

7-amino-2,3-dihydrol H- cyclopenta[ b] [l]benzothiophene-2-carboxylicethyl ester;

6-amino-2,3-dihydro-1H- cyclopenta[ b] [l]benzothiophene-Z-carboxylicacid;

5-chloro-2,3-dihydro-1H- cyclopenta[ b 1 l benzothiophene-2-carboxylicacid;

6-chloro-2,3-dihydro-1H- cyclopenta[b] [l]benzothiophene-Z-carboxylicacid;

8-chloro-2,3-dihydro-1H- cyclopenta[b][l]benzothiophene-Z-carboxylicacid;

7-nitro-2,3-dihydrol H- cyclopenta[b] [l]benzothiophene-2-carboxylicacid;

7-fluoro-2,3-dihydro-l H- cyclopenta[ b] [l]benzothiophene-2-carboxylicacid;

7-methyl-2,3-dihydro-1H- caracid

cyclopenta[b] [l]benzothiophene-2-carboxylic acid;

C ar- Scheme I.

acid

acid,

)n or R1" Id wherein HAL is halogen, for example, chlorine, fluorine,bromine and iodine, preferred is fluorine; R is.

hydrogen or an electron withdrawing group such as nitro,trifluoromethyl, lower alkoxy carbonyl, cyano or acyl, provided that atleast one of R is other than hydrogen, and R and n areas describedherein..

In Reaction Scheme I, the reaction of a halobenzene of formula II withan oxime of formula III to yield an O-phenyl oxime of formula IV isconveniently carried out in a polar solvent, such as dimethylsulfoxide,dimethylformamide, or hexamethylphosphoric triamide. The reactiontemperature is not critical. Preferably, the reaction is carried out ata temperature in the range of from about room temperature to about thereflux temperature of the reaction mixture. The molar ratio of thereactants is not critical. Preferably, they are reacted in a 1:1 molarratio.

The oxime of formula IV is converted to the compound of formula Idutilizing, for example, an acidic catalyst such as an organic, inorganicor Lewis acid, exemplary of which are hydrochloric acid, sulfuric acid,phosphoric acid, zinc chloride, copper chloride, boron trifluoride andthe like, and various combinations thereof. Conveniently the reactioncan be carried out in a polar solvent such as an alkanol, for example,methanol, ethanol, propanol, and the like, water or a hydrocarbon suchas benzene, toluene and the like. The reaction temperature is notcritical. Preferably, the reaction is carried out at a temperature inthe range of from about room temperature to about the reflux temperatureof the reaction mixture. The separation of the desired compound offormula Id from the reaction mixture can be effected utilizing knowntechniques such as, for example, filtration, crystallization,distillation and the like.

A nitro group present in the compound of formula Id can be converted toan amino group utilizing known procedures, for example, by catalyticreduction. An amino group can be converted to a diazonium salt utilizingknown procedures, for example, by reaction with sodium nitrite and amineral acid such as a hydrohalic acid. A diazonium group can then bereplaced by a halogen, cyano, hydroxy, lower alkoxy or hydrogenutilizing known procedures, for example, by mixing a diazonium saltsolution with, for example, a cuprous halide, cuprous cyanide, water, analkanol or a reducing agent, such as hypophosphorous acid, respectively,at room temperature or occasionally at elevated temperatures.

The preparation of compounds of formula I is also exemplified byReaction Scheme ll.

Scheme II wherein R,, X, n and r are as previously described, and R islower alkyl.

In Reaction Scheme II, a compound of formula V is alkylated with thecorresponding haloketocycloalkane carboxylic acid ester of formula VI toyield a compound of formula VII. The reaction is conveniently carriedout in a non-polar solvent, for example, a hydrocarbon, such as benzene,toluene and the like, or a polar solvent, such as dimethylsulfoxide,dimethylfonnamide, hexamethylphosphoric triamide, and the like. Thereaction temperature is not critical. Preferably, the reaction iscarried out at a temperature in the range of from about room temperatureto about the reflux temperature of the reaction mixture. The molar ratioof the reactants is not critical. Preferably, they are reacted at a 1:1molar ratio.

A compound of formula V1] is converted to a compound of formula Ie bythermal cyclization or by utilizing a cyclizing agent, such aspolyphosphoric acid, sulfuric acid, acetic acid, hydrochloric acid, andthe like. Preferably, the reaction is carried out at a temperature inthe range of from about 20 to about The reaction can be convenientlycarried out with or without a solvent. Exemplary of convenient solventsare acetic acid and the like.

The esters of formula Ie can be converted to the corresponding acid,i.e., the compounds of formula I wherein R is hydrogen, bysaponification according to known procedures, for example, by reactionwith an alkali metal hydroxide such as sodium hydroxide, potassiumhydroxide and the like, and subsequent treatment with a mineral acid,for example, a hydrohalic acid, such as hydrochloric acid and the like.

The separation of the desired compound of formula le and itscorresponding acid from the reaction mixture 4 m --cooR2' v Hal VI CHcooa VII (B1)!" 1 j-' coo can be effected utilizing known techniquessuch as, for

example, filtration, crystallization, distillation and the like.

Furthermore, a salt of an acid of formula I, i.e., a salt of compoundsof formula I wherein R is hydrogen, can be converted to a compound offormula I wherein R is amino-lower alkyl, mono-lower alkylamino-loweralkyl or di-lower alkylamino-lower alkyl by know procedures. Forexample, a salt of an acid of formula I is reacted with an amino-loweralkyl halide, monolower alkylamino-lower alkyl halide or di-loweralkylamino- VIII lower alkyl halide, exemplary of which are aminoethylchloride, methylamino-ethyl bromide, diethylaminomethyl chloride and thelike, to yield the desired end product. The temperature at which thereaction is effected is not critical; conveniently, the reaction iscarried out at a temperature in the range of from about roomtemperatureand about the reflux temperature of the reaction mixture. Conveniently,the reaction can be carried out in a polar solvent, such asdimethylformamide, dimethylsulfoxide or the like. The molar ratio ofreactants is not critical. Preferably, the reactants are utilized in a1:1 molar ratio.

The starting materials of formula II are known compounds or can beprepared in an analogous manner to known compounds. Exemplary of suchcompounds are:

4-fluoronitrobenzene; 4-fluorocyanobenzene; 4-fluoroacetophenone; andthe like The starting materials of formula III are known com- ,pounds orcan be prepared in an analogous manner to acid and methyl ester thereof;and the like.

Halogenation n COOR2 4-chlorophenol; S-chlorophenol; 4-nitrophenol;p-cresol; 4-chlorothiophenol The starting materials of formula VI can beprepared as exemplified in Reaction Scheme III:

Scheme III COOR;

HAL

The compounds of formula VIII are known compounds or can be prepared inan analogous manner to known compounds.

The halogenation is effected utilizing known procedures, for example,utilizing a halogen such as bromine in ether, at a temperature of l0C.Exemplary of such compounds are:

3-bromo-4-ketocyclohexanecarboxylic acid;

3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester;

2-bromo-3-ketocyclohexanecarboxylic acid;

4-bromo-5-ketocyclohexanecarboxylic acid;

3-bromo-4-ketocyclopentanecarboxylic acid;3-bromo-4-ketocyclopentanecarboxylic acid ethyl ester;

2-bromo-3-ketocyclopentanecarboxylic acid;

4-bromo-5-ketocyclopentanecarboxylic acid, and the like.

The intermediates of formula VII are novel compounds. Exemplary of suchcompounds are:

3-(4-chloro-phenoxy)-4-oxo-cyclohexane-carboxylic acid and ethyl esterthereof;

3-(4-chloro-phenylthio)-4-oxo-cyclohexanecarboxylic acid and ethyl esterthereof;

3-(4-chloro-phenoxy)-4-oxo-cyclopentanecarboxylic acid and methyl esterthereof;

3-(4-chloro-phenylthio)-4-oxo-cyclopentanecarboxylic acid and methylester thereof; and the like.

The compounds of formula I, when R is amino, mono-lower alkylamino ordi-lower alkylamino, and/or when R is amino-lower alkyl, mono-loweralkylaminolower alkyl or di-lower alkylamino-lower alkyl, form additionsalts with pharmaceutically acceptable organic or inorganic acids suchas hydrohalides, e.g., hydrochloride, hydrobromide, hydroiodide, othermineral acid salts such as sulfate, nitrate, phosphate and the like,alkyl-and mono-aryl sulfonates such as ethanesulfonate,toluene-sulfonate benzenesulfonate, or the like, other organic acidsalts, such as acetate, tartrate, maleate, citrate, benzoate,salicylate, ascorbate and the like.

The compounds of formula I, when R is carboxy and/or R is hydrogen, formsalts with pharmaceutically acceptable bases. Exemplary of such basesare alkali metal hydroxides, such as sodium hydroxide, potassiumhydroxide, and the like; alkaline earth hydroxides, such as calciumhydroxide, barium hydroxide and the like; sodium alkoxides, such assodium etholate, potassium etholate and the like; organic bases such aspiperidine, diethanolamine, N-methylglucamine and the like. Alsoincluded are the aluminum salts of the compounds of formula I, when R,is carboxy and/or R is hydrogen.

The compounds of formula 1, including the salts of those compounds offormula I which form salts with pharmaceutically acceptable bases andacids, possess anti-inflammatory activity and anti-rheumatic activity,and are therefore useful as anti-inflammatory agents and anti-rheumaticagents. Their pharmacologically useful activities are demonstrated inwarmblooded animals using standard procedures.

For example, the anti-inflammatory activity is demonstrated in Albinorats of Hart Strain, weighing 125-l 55 gms. The test animals are given10 ml. of vehicle which contains the test compound per kg. of bodyweight. The animals are treated daily for consecutive days. Three hoursafter the first treatment, 0.05 ml. of an 0.5 percent suspension of heatkilled dessiccated Mycobacterium butyricum in U.S.P. olive oil, whichhas been steam sterilized for 30 minutes, is injected into the righthind foot of each rat. The paw volume is measured immediately after theinjection of the adjuvant and again 96 hours later. The difference isrecorded as volume of edema. The paw volume is measured by immersion ofthe paw into a column of mercury to an ink mark exactly at the level ofthe lateral malleolus. Percent inhibition is calculated by dividing theaverage control edema minus the average treatment edema by the averagecontrol edema times 100. The percent inhibition is plotted against doseon semi-logarithmic probability paper and the dose required to produce a30 percent reduction in edema is estimated therefrom and is expressed asED30.

I-lilgar, A. G. and Hummel, D. J.: Endocrine Bioassay Data, No. 1, p.15, August 1964 (Cancer Chemotherapy National Service Center, N.I.H.)

When 7-chloro- 1 ,2-dihydro-3 4H )-dibenzofuran carboxylic acid isutilized as the test substance at a dosage of 11.5 mg. p.o., ananti-inflammatory activity is observed (ED 11.5).

The compounds of formula 1, their enantiomers and salts as hereindescribed, have effects qualitatively similar to those ofphenylbutazone, known for its therapeutic uses and properties. Thus, thecompounds of this invention demonstrate a pattern of activity associatedwith anti-inflammatory agents of known efficacy and safety. 4

The compounds of formula I, their enantiomers and salts as hereindescribed can be incorporated into standard pharmaceutical dosage forms,for example, they are useful for oral or parenteral application with theusual pharmaceutical adjuvant material, for example, organic orinorganic inert carrier materials such as water, gelatin, lactose,starch, magnesium stearate, talc, vegetable oils, gums,polyalkylene-glycols and the like. The pharmaceutical preparations canbe employed in a solid form, for example, as tablets, troches,suppositories, capsules, or in liquid form, for example, as solutions,suspensions or emulsions. Pharmaceutical adjuvant materials can be addedand include preservatives, stabilizers, wetting or emulsifying agents,salts to change the osmotic pressure or to act as buffers. Thepharmaceutical preparations can also contain other therapeuticallyactive substances.

Since the compounds of the invention possess asymmetric carbon atoms,they are ordinarily obtained as racemic mixtures. The resolution of suchracemates into the optically active isomers can be carried out by knownprocedures. Some racemic mixtures can be precipitated as eutectics andcan thereafter be separated. Chemical resolution is, however, preferred.By this method, diastereomers are formed from the racemic mixture withan optically active resolving agent, for example, an optically activebase, such as d-a-(l-naphthyl)ethylamine, which can be reacted with thecarboxyl group. The formed diastereomers are separated by selectivecrystallization and converted to the corresponding optical isomer. Thus,the invention covers the racemates of the compounds of formula I as wellas their optically active isomers.

The following examples further illustrate the invention. Alltemperatures are in degrees Centigrade, unless otherwise mentioned.

Example 1 preparation of anecarboxylic acid A mixture of 12.1 g. ofpotassium t-butoxide and 8.5 g. of 3-oxyminocyclohexanecarboxylic acidin ml. of dimethylsulfoxide was treated with 5.73 ml. of 4-fluoronitrobenze ne, stirred vigorously at room temperature for 2 hours,diluted with 450 ml. of saturated sodium chloride solution and acidifiedwith acetic acid. The precipitate was removed by filtration, washedsuccessively with water and pentane, and dried to give 14.25 g. of 3-(4-nitrophenoxyimino cyclohexanecarboxylic acid as light yellow crystals,m.p. l4615 1 dec. This material can be used for the next step withoutpurification. Recrystallized from methylene chloride ether,3-(4-nitrophenoxyimino)cyclohexanecarboxylic acid has a melting point ofl58.5-159 dec. Analysis calcd. for C H N O (278.26)

C, 56.11; H, 5.07; N, 10.07

Found: C, 56.42; H, 5.08; N, 10.37

Example 2 Preparation of1,2-dihydro-8-nitro-3(4H)-dibenzofurancarboxylic acid A solution of 23.4g. of 3-(4-nitrophenoxyimino)cyclohexanecarboxylic acid in 250 ml. ofacetic acid containing 29 g. of hydrogen chloride was stirred at 90 for3-(4-nitrophenoxyimino)cyclohex- 17 hours. Thereafter, the reactionmixture was cooled to 30 and filtered. The solid residue was washedsuccessively with acetic acid, hexane and water, and dried to give 8.5g. of l,2-dihydro-8-nitr0-3(4H)-dibenzofurancarboxylic acid as tancrystals, m.p. 229231.5. This material can be used for the next stepwithout purification. Recrystallized from acetoneether, 1,2-dihydro-8-nitro-3(4H)-dibenzofurancarboxylic acid has a melting pointof 226230. Analysis Calcd. for C I-I NO (261.24)

C, 59.77; H, 4.24; N, 5.36

Found: C, 59.57; H, 4.22; N, 5.51

9 Example 3 Preparation of8-amino-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid A solution of 4.83g. of 1,2-dihydro-8-nitro-3(4H)- dibenzofurancarboxylic acid in ml. ofacetic acid was reduced in the Brown hydrogenator with 1 g. of 10percent palladium-on-charcoal catalyst. The catalyst was removed byfiltration. The filtrate was evaporated, and the residue wascrystallized from acetonitrile-ether to give 3.4 g. of8-amino-l,2-dihydro- 3(4H)-dibenzofurancarboxylic acid as browncrystals, mp. 235 235.5dec. This material may be used in succeedingsteps without further purification. Crystallized from'acetonitrile-ether as light brown crystals, 8-amino-l ,2-dihydro-3(4H)-dibenzofurancarboxylic acid has a melting point of23l231.5 dec. Analysis Calcd. for c H NO (231.25)

C, 67.52; H, 5.67; N, 6.06

Found: C, 67.35; H, 5.68; N, 6.05

Example 4 Preparation of8-amino-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid ethyl esterhydrochloride A solution of 1 g. of 8-amino-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid in 100 ml. of ethanol saturated withhydrogen chloride was heated at reflux temperature for 2 hours and thenevaporated to dryness. The residue was crystallized from ethanol-etherto give 986 mg. (89 percent) of 8-amino-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid ethyl ester hydrochloride as white crystals,m.p. 25025 1 dec. Crystallized from ethanol-ether as white crystals,8-amino-1,2-dihydro- 3(4H)-dibenzofurancarboxylic acid ethyl esterhydrochloride has a melting point of 251252 dec. Analysis Calcdjfor C HNO .HCl (295.77)

C, 60.91; H, 6.13; N, 4.74

Found: C, 61.11; H, 6.28; N, 4.91

Example 5 Preparation of 3-bromo-4-ketocyclohexanecarboxylic acid ethylester A solution of 40 g. of 4-ketocyclohexanecarboxylic acid ethylester in 650 ml. of ether was stirred at during the dropwise addition of12.05 ml. of bromine. The resultant colorless solution was washedsuccessively with water, saturated sodium bicarbonate solution, andagain with water. The organic layer was dried over sodium sulfate andevaporated to give 59 g. of 3- bromo-4-ketocyclohexanecarboxylic acidethyl ester as a colorless oil. This material may be used for the nextistep without further purification, and may be kept for 2 to 3 daysunder nitrogen, without significant decomposition. For analysis, asample was distilled, b.p. 95/0.001 mm. Analysis Calcd. for C H BrO(249.11)

Found: C, 43.24; H, 5.22

Example 6 Preparation of 8-chloro-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid Method A:

A suspension of 2 g. of 8-amino-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid in 12 ml. of water and ml. of concentratedhydrochloric acid, stirred at 0, was treated dropwise with a coldsolution of 716 mg. of sodium nitrite in 20 ml. of water. Thediazotization solution was stirred at 0 for 30 minutes and then wasadded I gradually to a cold solution of 1.3 g. of cuprous chlo- ;ride in18 ml. of concentrated hydrochloricacid. The :mixture was stirred for2.5 hours at room temperature, {diluted with water, and filtered to give1.78 g. of 8- ichloro-l ,2-dihydro-3(4H)-dibenzofurancarboxylic iacid astan crystals, m.p. l94l98.5. A pure sample ',of 8-ch1oro-1 ,2-dihydro-3(4H )-dibenzofurancarboxyllic acid as white crystals, m.p. l98201, wasobtained ,in about 50 percent yield by sublimation at 190/0.05

Found: C, 62.24; H, 4.35; N, 13.76 Method B:

A suspension of sodium 4-chlorophenoxide, prepared from 11.6 g. of4-chlorophenol and 4.86 g. of sodium methoxide, and 22.5 g. of3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester in 300 ml. ofbenzene was stirred for 64 hours at room temperature. The mixture wasthen washed successively with 1N sodium hydroxide and water. The organiclayer was dried over sodium sulfate and evaporated to give 18.30 g. of3-(pchlorophenoxy)-4-oxocyclohexanecarboxylic acid ethyl ester as ayellow oil. A mixture of 18.25 g. of this material and 180 g. ofpolyphosphoric acid was stirred for 10 minutes at room temperature andthen quenched with ice and water. The resulting solution was extractedwith ether. The organic layer was washed successively with 1N sodiumhydroxide and water, dried and evaporated to give 15.6 g. of viscousoil, which, after distillation, gave 10.2 g. of8-chloro-1,2-dihydro-3(4H)- dibenzofurancarboxylic acid ethyl ester as alight yellow oil, b.p. 175185/l mm. A solution of 10.2 g. of 8-chloro-1,2-dihydro-3 4H )-dibenzofurancarboxylic acid ethyl ester, 150 ml. of 1Nsodium hydroxide and 300 ml. of ethanol was heated at reflux temperaturefor 1.5 hours and then concentrated at reduced pressure. Afterextraction with methylene chloride, the aqueous layer was treated withcharcoal and filtered. The filtrate was cooled in ice water andacidified with 25 m1. of concentrated hydrochloric acid. The precipitatewas filtered, washed with water, and dried to give 7 g. of crystals,m.p. 199.5-201, which were identical with the 8-chloro- 1,2-dihydro-3(4H)-dibenzofurancarboxylic acid obtained by Method A.

Example 7 Preparation of8-fluoro-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid A suspension ofsodium p-fluorophenoxide, prepared from 11.2 g. of p-fluorophenol, 5.4g. sodium methoxide and 26.8 g. of 3-bromo-4-ketocyclohexanecarboxylicacid ethyl ester in 200 ml.'of benzene was stirred for 16 hours at roomtemperature. The reaction mixture was washed with water, 1N sodiumhydroxide, and saturated sodium chloride solution, and was dried oversodium sulfate. Evaporation of the solvent gave 22.1 g. of3-(p-fluorophenoxy)-4-oxocyclohexanecarboxylic acid ethyl ester.

A mixture of 17.1 g. of this material and 150 g. of

polyphosphoric acid was stirred for 10 minutes at room temperature, thenquenched with ice water and extracted three times with ether. Theorganic portion washed with sodium bicarbonate and saturated sodiumchloride solutions, dried, and evaporated to dryness to give 15.8 g. ofan oil which was distilled in a Kugelrohr oven" to give 7.75 of8-fluoro-1,2-dihydro-3(4H)- dibenzofurancarboxylic acid ethyl ester as acolorless oil. This material was heated at reflux temperatures for 1hour in a mixture of ml. of ethanol and 50 ml. of 1N sodium hydroxide.The ethanol was evaporated under reduced pressure. After the addition of50 ml. of water, the reaction mixture was treated with charcoal andneutralized with 25 ml. of 2N hydrochloric acid. The solids which formedwere removed by filtration and crystallized from acetone-water to give3.65 g. of 8-fluoro-1 ,2-dihydro-3(4H)-dibenzofurancarboxylic acid aswhite crystals, m.p. 208-2l0.

Analysis Calcd. for C l-L FO; (234.23)

C, 66.66; H, 4.73 Found: C, 66.68; H, 4.93

Example 8 Preparation of8-methyl-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid A suspension ofsodium p-cresolate, prepared from 3.24 g. of p-cresol and 1.62 g. ofsodium methoxide, and 7.45 g. of 3-bromo-4-ketocyclohexanecarboxylicacid ethyl ester in 100 ml. of dry benzene was stirred for 64 hours atroom temperature. The mixture was then washed successively with water,1N sodium hydroxide and water. The aqueous layers were extracted twotimes with benzene. The organic layers were dried .over sodium sulfateand evaporated to give 6.11 g. of

3-(p-methylphenoxy )-4-oxocyc1ohexanecarboxylic acid ethyl ester as ayellow oil.

A solution of 1.9 g. of the above material in 5 ml. of ether wascombined with 19 g. of polyphosphoric acid and stirred for 20 minutes atroom temperature under nitrogen. The reaction was quenched by additionof ice water, and the resulting mixture was stirred until a solution wasobtained. This solution was extracted three times with ether. Theorganic layers were washed with water, saturated sodium bicarbonatesolution, water, and dried over sodium sulfate. Evaporation of thesolvent gave 1.62 g. of a yellow oil which was distilled under vacuum togive 1.2 g. of 8-methyl-l,2-dihydro- 3(4H)-dibenzofurancarboxy1ic acidethyl ester. A solution of this material (1.2 g.) in 9 ml. of 1N sodiumhydroxide, and 9 ml. of ethanol was heated at reflux temperature for 1hour under a nitrogen atmosphere. The ethanol was removed under vacuum.The residue was dissolved in water, treated with charcoal, and filtered.The filtrate was cooled in an ice water bath and acidified with 2Nhydrochloric acid. The precipitate which formed was filtered andcrystallized from etherpentane to give 250 mg. of 8-methyl-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid, m.p. l99-201. Analysis Calcd. for C HO (230.26)

Found: C, 72.65; H, 6.31

Example 9 Preparation of6-chloro-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid To a solution of6.43 g. of freshly distilled 2- chlorophenol in 100 ml. of methanol wasadded 2.7 g. of sodium methoxide, and the resulting solution wasevaporated to dryness under reduced pressure to give 7.5 g. of sodium2-chlorophenoxide. A suspension of the above sodium salt and of 12.5 g.of 3-bromo-4- ketocyclohexanecarboxylic acid ethyl ester in 150 m1. ofbenzene was stirred overnight at room temperature. The reaction mixturewas washed with two 50 ml. portions of water, two 50 ml. portions of 1Nsodium hydroxide, and three 50 ml. portions of brine. The organic layerswere dried over sodium sulfate and evaporated to dryness to give 1 1.85g. of 3- (ochlorophenoxy)-4-oxocyclohexanecarboxylic acid ethyl ester asa dark yellow oil.

A mixture of 1 g. of 3-(o-chlorophenoxy)-4-oxocyclohexanecarboxylic acidethyl ester and 10 g. of polyphosphoric acid was stirred for 1 hour at75. After the addition of 25 ml. of ice water, the reaction mixture wasextracted three times with 100 ml. portions of ether. The organic layerswere washed with water, 1N sodium bicarbonate and with brine. The etherextracts were dried over sodium sulfate, evaporated to dryness, and theresidue (955 mg.) was distilled in a Kugelrohr oven at 200/0.2 mm. togive 475 mg. of 6-chloro-l ,2- dihydro-3(4H)-dibenzofurancarboxylic acidethyl ester Preparation as a yellow oil. A solution of this material in10 ml. of ethanol and 5 ml. of 2N sodium hydroxide was heated at refluxtemperature for 1 hour. After removal of the ethanol, the resultingcloudy solution was treated with charcoal, filtered and treated with 5ml. of 2N HCl. The solids which formed were removed by filtration andcrystallized from acetonitrile to give 250 mg. of 6- chloro-l,2-dihydro-3 4H )-dibenzofurancarboxylic acid as white crystals, m.p.188l92C. Recrystallization from acetone-water gave 230 mg. of6-chlorol,2-dihydro-3(4H)-dibenzofurancarboxylic acid, m.p. l-193C.Analysis Calcd. for C H ClQ, (250.68)

Found: C, 61.99; H, 4.29

Example 10 Preparation of7-chloro-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid and9-chloro-1,2-dihydro- 3(4H)-dibenzofurancarboxylic acid 7 Sodium3-chlorophenoxide, prepared from 11.6 g. of 3-chlorophenol and 4.86 g.of sodium methoxide, in 300 ml. of dry benzene was stirred for 10 hoursat room temperature with 21 g. of 3-bromo-4-ketocyclohexanecarboxylicacid ethyl ester. The suspension was washed twice with ml. portions ofwater, once with 100 m1. of 1N sodium hydroxide, and thrice with 100 ml.portions of water. The aqueous layers were extracted twice with ml.portions of benzene. The combined organic layers were dried with sodiumsulfate and evaporated to give 20.4 g. of 3-(3-chlorophenoxy)-4-oxocyclohexanecarboxylic acid ethyl ester. A mixture of5.63 g. of this material and 85 g. of polyphosphoric acid was stirred at75 for 1 hour, decomposed with ice and water, and extracted three timeswith 250 ml. portions of ether. The organic layers were washed twicewith 200 ml. portions of water, once with 150 ml. of saturated sodiumbicarbonate solution, and three times with 200 ml. portions of water,and were then dried with sodium sulfate and evaporated to give 4.5 g. ofbrown oil. Distillation at /0.2 mm. gave 3.5 g. of a mixture of theisomeric esters 7-chloro- 1,2-dihydro-3(4H)-dibenzofurancarboxylic acidethyl ester and 9-chloro-1,2-dihydro-3(4H)-dibenzofurancarboxylic acidethyl ester. A solution of 3.48 g. of this material in 70 ml. of 1Nsodium hydroxide and 140 ml. of ethanol was stirred at refluxtemperature for 1 hour and then evaporated. The residue was dissolved inwater, stirred with charcoal and filtered. The filtrate was acidifiedwith concentrated hydrochloric acid, and the resulting precipitate wascollected to give 2.72 g. of an isomeric mixture of7-chloro-1,2-dihydro-3(4H)- dibenzofurancarboxylic acid and 9-chloro-l,2-dihydro- 3(4H)-dibenzofurancarboxylic acid as a gray solid, mp.148163. Recrystallization from ether-pentane gave 1.51 g. of theisomeric mixture 7-chloro-l,2- dihydro-3(4H)-dibenzofurancarboxylic acidand 9- chloro- 1 ,2-dihydro-3 (4H )-dibenzofurancarboxylic acid asyellowish crystals, m.p. l52-l80. Crystallized from methylenechloride-ether-pentane; 7-chloro-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid and 9- chloro-l ,2-dihydro-34H)-dibenzofurancarboxylic acid as white crystals had a melting point ofl67-l 85. Analysis calc. for C H ClO (250.68)

Found: C, 62.38; H, 4.68

Example 1 1 of 9-chloro-1 ,2-dihydro-3(4H)-dibenzofurancarboxylic acidmethyl ester A solution of 5.65 g. of the mixture of isomers 7- chloro-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid and 9-chloro- 1,2-dihydro-3(4H)-dibenzofurancarboxylic acid, m.p. 13l-155, in 100 ml ofmethanol saturated with hydrogen chloride was stirred at refluxtemperature for 1 hour. Evaporation of the solvent and crystallizationof the residue from ether-pentane gave 884 mg. of9-chloro-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid methyl ester asyellowish crystals, m.p. 99-102. A sample for analysis was sublimed at90-100/0.l2 mm. as white crystals, m.p. 101-102.5. Analysis Calcd. for CH ClO (264.71)

Found: C, 63.35; H, 4.82

Example 12 Preparation of9-chloro-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid A solution of 840mg. of 9-chloro-1,2-dihydro- 3(4H )-dibenzofurancarboxylic acid methylester in 15 ml. of 1N sodium hydroxide and 30 ml. of ethanol was stirredat reflux temperature for 1 hour and then evaporated. The residue wasdissolved in water and extracted three times with 75 ml. portions ofmethylene chloride. The aqueous layer was stirred with charcoal, andfiltered, and the filtrate was acidified with concentrated hydrochloricacid. The precipitate was filtered, dried and crystallized fromtetrahydrofuran-ether-pentane to give 452 mg. of9-chloro-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid as whitecrystals, m.p. l89-190. Analysis Calcd. for C H ClO (250.68)

Found: C, 62.51; H, 4.51

Example 13 Preparation of 7-acetamido-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid ethyl ester A suspension of15.1 g. of 3-acetamidophenol and 13.8 g. of potassium carbonate in 60ml. of dimethyl-.

'with ether. The ether extracts were washed with 1N sodium hydroxide,water, and dried over sodium sulfate. Evaporation of the solvent gave18.0 g. of 3-(macetamidophenoxy)-4-oxocyclohexanecarboxylic acid ethylester. A mixture of 16 g. of this material and 160 g. of polyphosphoricacid was stirred for 30 minutes at room temperature. An excess of icewater was added. The precipitate which formed was filtered, dried,dissolved in methylene chloride, and filtered through a column ofalumina (activity grade II). The methylene chloride eluates wereevaporated to give 11.1 g. of an oil which was crystallized frommethylene chlorideether-pentane to give 4.5 g. of 7-acetamido-l ,2-dihydro-3(4H)-dibenzofurancarboxylic acid ethyl ester, m.p. 115ll6.Analysis Calcd. for C -,H NO (301.33)

C, 67.76; H, 6.36; N, 4.65

Found: C, 68.07; H, 6.35; N, 4.62

Example 14 Preparation of7-amino-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid ethyl esterhydrochloride A solution of 2.9 g. of 7-acetamido-l ,Z-dihydro-3(4H)-dibenzofurancarboxylic acid ethyl ester in ethanolic hydrogenchloride was heated at reflux temperature for 2 hours. The solvent wasremoved under vacuum. Crystallization of the residue from ethanol-ethergave 2.2 g. of 7-amino-1,2-dihydro-3(4H)-dibenzofurancarboxylic acidethyl ester hydrochloride, m.p. 226228. Analysis Calcd. for C H NO .HCl(295.75)

C, 60.91; H, 6.13; N, 4.74

Found: C, 60.62; H, 6.24; N, 4.64

Example 15 Preparation of7-chloro-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid A solution of 145mg. of sodium nitrite in 2 ml. of water was added dropwise, undernitrogen, to a cooled solution of 590 mg. of 7-amino-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid ethyl ester hydrochloride in 5 ml. of aceticacid:water (1:1). The resulting solution was added dropwise, undernitrogen, to a suspension of 238 mg. of cuprous chloride in 2 ml. ofcone. hydrochloric acid at 5. The reaction mixture was stirred at roomtemperature for 30 minutes, then extracted three times with ether. Theether layers were washed with 1N hydrochloric acid, 1N sodium hydroxide,water, and dried over sodium sulfate. Evaporation of the solvent gave510 mg. of an oil, which was distilled in a Kugelrohr oven, to give 444mg. of 7-chloro- 1,2-dihydro-3(4H)-dibenzofurancarboxylic acid ethylester as a yellow oil. A solution of 420 mg. of this material, 5 ml. of1N sodium hydroxide, and 10 ml. of ethanol was heated at refluxtemperature for 1 hour. The solvent was removed under vacuum. Theremaining residue was dissolved in water. The aqueous solution wasextracted two times with ether, cooled and aciditied with 2Nhydrochloric acid. The precipitate which formed was filtered andcrystallized from acetonewater to give 290 mg. of a solid, m.p. 189-191.This material was recrystallized from acetone-ether to give 110 mg. of7-chloro-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid, m.p. 194-196.Analysis Calcd. for C H ClO; (250.68)

Found: C, 62.33; H, 4.22

Example 16 Preparation of7-acetamido-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid A solution of1.2 g. of 7-acetamido-l ,2-dihydro- 3(4H)-dibenzofurancarboxylic acidethyl ester, 10 ml. of 1N sodium hydroxide, and 10 ml. of ethanol washeated at reflux temperature for 1 hour. The solvent was removed undervacuum. The residue was dissolved in water and acidified with 2Nhydrochloric acid. The precipitate was filtered and crystallized fromacetonewater to give mg. of 7-acetamido-l ,2-dihydro-3(4H)-dibenzofurancarboxylic acid, m.p. 229230. Analysis Calcd. for C H,NO (273.28)

C, 65.92; H, 5.53; N, 5.13

Found: C, 65.71; H, 5.26; N, 4.98

- Example 17 Preparation of7-amino-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid hydrochloride Asolution of mg. of 7-amino-l,2-dihydro- 3(4H)-dibenzofurancarboxylicacid ethyl ester hydrochloride, 3 ml. of 1N sodium hydroxide 'and 10 ml.of ethanol was heated at reflux temperature for 1 hour. The solvent wasremoved under vacuum. The residue was dissolved in water, cooled, andacidified with 1N hydrochloric acid. The solid was filtered andcrystallized from methanol/ether to give 45 mg. of7-aminol,2-dihydro-3(4H)-dibenzofurancarboxylic acid hydrochloride, m.p.290300. Analysis Calcd. for C,;,H NO .HCl (267.70)

C, 58.33; H, 5.27; N, 5.23; Cl, 13.24

Found: C, 58.32; H, 5.48; N, 5.14; Cl, 13.37

Example 18 Preparation of7-methoxy-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid A suspension of6.2 g. of freshly distilled 3- methoxyphenol and 6.9 g. of potassiumcarbonate in 20 ml. of dimethylformamide was heated at 100 for 15minutes. To the stirred suspension was added dropwise 12.5 g. of3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester in 5 ml. ofdimethylformamide, and the resulting mixture was stirred at 100 for 30minutes. After cooling, 150 ml. of water was added, and the reactionmixture was extracted with three 150 ml. portions of ether. The etherlayers were washed with 1N sodium hydroxide and water, dried over sodiumsulfate, and

7 treated with charcoal. Evaporation of the'solvent gave 8.5 g. of3-(m-methoxyphenoxy)-4-oxocyclohexanecarboxylic acid ethyl ester as ayellow oil. A mixture of this material and 85 g. of polyphosphoric acidwas stirred for minutes at room temperature, and added to 150 ml. of icewater. Thereafter, the mixture was extracted with three 150 ml. portionsof ether. The ether extracts were washed with saturated aqueous sodiumbicarbonate and brine, and dried over sodium sulfate. Evaporation of thesolvent gave 7 g. of 7-methoxy-1,2- dihydro-3(4H)-dibenzofurancarboxylicacid ethyl ester as a dark oil, which was dissolved in 100 ml. ofethanol and 50 ml. of 2N sodium hydroxide. The resulting solution washeated at reflux temperature for 1 hour. The ethanol was removed underreduced pressure. After the addition of 150 ml. of water, the reactionmixture was extracted with ether. The aqueous layer was treated withcharcoal, cooled in an ice water bath, and neutralized with 50 ml. of 2Nhydrochloric acid. The solids which formed were removed by filtrationand were crystallized from acetone-water to give 3.8 g. of crystals,m.p. 175-180. Recrystallization from acetonitrile-water gave7-methoxy-1,2-dihydro-3(4H)- dibenzofurancarboxylic acid as whitecrystals, m.p. l8ll83.

Analysis Calcd. for C I-1 0 (246.25)

C, 68.28; H, 5.73 Found: C, 68.45; H, 5.91

Example 19 Preparation of 7,9-dimethoxy-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid A suspension of 3.08 g. of 3,5-dimethoxyphenol, 2.76 g. of potassium carbonate and 4.98 g. of3-bromo-4- ketocyclohexanecarboxylic acid ethyl ester in 30 ml. ofdimethylformamide was stirred at 100 for 2 hours. Thereafter, 150 ml. ofice water was added, and the resulting solution was extracted 3 timeswith 100 ml. portions of ether. The ether layers were washed with 1Nsodium hydroxide and with water, dried over sodium sulfate, andevaporated to dryness. The residue (3.3 g.)3-(3,S-dimethoxyphenoxy)-4-oxocyclohexanecarboxylic acid ethyl ester wasstirred at room temperature for 15 minutes with 33 g. of polyphosphoricacid. After the addition of 150 ml. of water, the reaction mixture wasextracted three times with 100 ml. portions of ether. The ether layerswere washed with sodium bicarbonate and saturated sodium chloridesolutions, dried over sodium sulfate, and evaporated to dryness to give2.7 g.

of 7,9-dim ethoxy-l ,2-dihydro-3 (4H )-dibenzofurancarboxylic acid ethylester. This material was dissolved in 50 ml. of ethanol and 25 ml. of 2Nsodium hydroxide, and the resulting solution was heated at refluxtemperature for 1 hour. The reaction mixture was cooled, and the ethanolwas removed under reduced pressure. The residue which formed was dilutedwith water, treated with charcoal, cooled in an ice bath and neutralizedwith 25 ml. of 2N hydrochloric acid. The solids which formed wereremoved by filtration and crystallized from acetone-water to give 1 g.of 7,9-dimethoxy-l ,2- dihydro-3(4H)-dibenzofurancarboxylic acid, m.p.194196. Analysis Calcd. for C ,-,H, O (276.29)

Found: C, 65.13; H, 5.95

Example 20 Preparation of7,9-dichloro-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid A solution of3.12 g. of 3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester in 5 ml.of dimethylformamide was added dropwise to a suspension of 2.04 g. of3,5-dichlorophenol and 0.865 g. of potassium carbonate in 25 ml. ofdimethylformamide. The resulting mixture was heated for 2 hours atThereafter, it was cooled to room temperature, diluted with water, andextracted three times with ether. The organic layers were washed withwater, saturated sodium bicarbonate solution, and water, dried oversodium sulfate, and evaporated to give 3.7 g. of3-(3,5-dichlorophenoxy)- 4-oxocyclohexanecarboxylic acid ethyl ester.This material was combined with 38 g. of polyphosphoric acid and heatedfor 1 hour at 70. The reaction was quenched by addition of ice water,and the resulting solution was extracted three times with ether. Theorganic layers were washed with water, saturated sodium bicarbonatesolution, and water, dried over sodium sulfate, and evaporated to give2.7 g. of 7,9-dichloro-1,2- dihydro-3(4H)-dibenzofurancarboxylic acidethyl ester. A solution of 2.7 g. of 7,9-dichloro-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid ethyl ester, 25 ml. of 1N sodiumhydroxide, and 25 ml. of ethanol was heated at reflux temperature for 1hour. The ethanol was removed under vacuum. The residue was dissolved inwater, extracted two times with ether, cooled in an ice water bath, andacidified with 2N hydrochloric acid. The precipitate which formed wasfiltered and dried under vacuum to give 2.0 g. of a solid, m.p.

190-200. Crystallization from acetone-ether gave 1.06 g. of7,9-dichloro-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid, m.p.223-225. Analysis Calcd. for C H Cl O (285.13)

Found: C, 54.65; H, 3.86

Example 21 Preparation of 3-(4-cyanophenoxyimino)cyclohexanecarboxylicacid To a solution of 2.26 g. of potassium t-butoxide in 18 ml. ofdimethylsulfoxide, stirred vigorously at room temperature, was added1.57 g. of 3-oxyiminocyclohexanecarboxylic acid. After 15 minutes, themixture was treated with 1.21 g. of p-fluorobenzonitrile, stirred for 2hours, diluted with ml. of saturated sodium chloride solution, andacidified with acetic acid. The solid which formed was removed byfiltration,

dried and crystallized from tetrahydrofuran-ether-,

pentane to give 1.6 g. of 3-(4-cyanophenoxyimino)cy- Preparation 21clohexanecarboxylic acid as white crystals, m.p. l5.3154. AnalysisCalcd. for C H N O (258.28)

C, 65.10; H, 5.46; N, 10.85 Found: C, 65.01; H, 5.48; N, 10.87

Example 22 of 8-cyano-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid Asolution of 258 mg. of 3-(4- cyanophenoxyimino)cyclohexanecarboxylicacid in 25 ml. of acetic acid saturated with hydrogen chloride washeated on a steambath overnight, and then evaporated to dryness. Theresidue was digested on the steambath with 3 ml. of acetic acid.Thereafter, the mixture cooled to 25, and the solid which formed wasremoved by filtration to give 99 mg. of 8-cyano-1,2-dihydro-'3(4H)-dibenzofurancarboxylic acid as white crystals,

m.p. 25 3-255. Crystallized from tetrahydrofuranether-pentane, as whitecrystals, 8-cyano-1,2-dihydro- 3(4H)-dibenzofurancarboxylic acid had amelting point of 249250. Analysis Calcd. for C H NQ, (241.26)

C, 69.70; H, 4.59; N, 5.80

Found: C, 69.69; H, 4.60; N, 5.77

Example 23 Preparation of 8-cyano-3,4-dihydro-1(2H)-dibenzofurancarboxylic acid I Fractionalcrystallization of g. of the mother liquo rs obtained from thepreparation of 8-cyano-1,2- dihydro-3(4H)-dibenzofurancarboxylic acidgave 4.5 g. of a tan solid, m.p. 185l90. Two g. of this material wasfiltered through a column of 8 g. of Florisil. The column was elutedsuccessively with benzene, methylene chloride, ether and ethyl acetate.The methylene chloride and the ether eluates were combined andcrystallized twice from methylene chloride-ether-pentane to give 340 mg.of 8-cyano-3,4-dihydro-l(2H)-dibenzofurancarboxylic acid, m.p. 195-196.

Analysis Calcd. for C H NO (241.26)

C, 69.70; H, 4.59; N, 5.80

Found: C, 69.75; H, 4.73; N, 5.81

Example 24 Preparation of S-carbamoyl-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid ethyl ester A suspension of1 g. of 8-cyano-l,2-dihydro-3(4H)- dibenzofurancarboxylic acid in 100ml. of ethanol was stirred in an ice water bath and was saturated withhydrogen cloride. The mixture was refrigerated overnight and then heatedto reflux temperature for 4 hours with the introduction of hydrogenchloride. The solution was evaporated to dryness, and the residue waspartitioned between methylene chloride and dilute sodium hydroxide. Theorganic layer was washed with water,

dried and evaporated to give 1.1 g. of solid, which was crystallizedfrom methylene chloride-ether to give 283 mg. of 8-carbamoyl-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid ethyl ester as whitecrystals, m.p. 206.5 207.5". Crystallized twice from methylenechloride-ether as white crystals, 8-carbamoyl-l ,2-dihydro-3(4H)-dibenzofurancarboxylic acid ethyl ester had a meltingpoint of 207.5 208. Analysis Calcd. for C H NQ, (287.33)

C, 66.88; H, 5.97; N, 4.87

Found: C, 67.01; H, 5.69; N, 4.85

Example 25 Preparation of 1,2-dihydro-3(4H),8-dibenzofurandicarboxylicacid A mixture of 250 mg. of 8-cyano-1 ,2-dihydro-3( 4Hdibenzofurancarboxylic acid and 3 ml. of a percent solution of potassiumhydroxide in water was heated for 3 hours at 100. The solution thusobtained was diluted with water, cooled in an ice water bath, andacidified with 2N hydrochloric acid. The precipitate which formed wasfiltered and dried under vacuum. The solid obtained was crystallizedfrom methanol to give 75 mg. of1,2-dihydro'3(4H),8-dibenzofurandicarboxylic acid, m.p. 322323. Anadditional 130 mg. of product, m.p. 321-322, was obtained from themother liquors. Analysis Calcd. for C H O (260.24)

Found: C, 64.39; H, 5.01

Example 26 Preparation of8-cyano-3,4-dihydro-2(1H)-dibenzofurancarboxylic acid To asolution of1.47 g. of potassium t-butoxide in 11 ml. of dimethylsulfoxide stirredvigorously at room temperature, was added 993 mg. of4-oxyiminocyclohexanecarboxylic acid. After 20 minutes, the reac-- tionmixture was treated with 754 mg. of 4- fluorobenzonitrile, stirred for 2hours, diluted with ml. of saturated sodium chloride solution andacidified with acetic acid. Precipitate was removed by filtration,washed with water and with pentane and dried to give 670 mg. of4-(4-cyanophenoxyimino)- cyclohexanecarboxylic acid as a tan powder,m.p. -161 dec. This material can be used in the succeeding step withoutfurther purification.

A solution of 570 mg. of 4-(4-cyanophenoxyimino) cyclohexanecarboxylicacid in 10 ml. of acetic acid saturated with hydrogen chloride washeated on a steambath for 15 hours. The reaction mixture was cooled toabout 25, and the solid which formed was removed by filtration.Crystallization from tetrahydrofuran-ether gave 230 mg. of8-cyano-3,4-dihydro-2(1H)-dibenzofurancarboxylic acid as white crystals,m.p. 251251.5. Recrystallized from tetrahydrofuranether as whitecrystals, 8-cyano-3,4-dihydro-2(1H)- dibenzofurancarboxylic acid had amelting point of 249.5 250.5.

Analysis Calcd. for C H NQ, (241.26)

C, 69.70; H, 4.59; N, 5.80

Found: C, 69.85; H, 4.72; N, 5.81

Example 27 Preparation of8-acetyl-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid To a solution of9 g. of potassium t-butoxide in 50 ml. of dimethylsulfoxide, stirredvigorously at room temperature under a nitrogen atmosphere, was added6.3 g. of 3-oxyiminocyclohexanecarboxylic acid. After 30 minutes, themixture was treated with 4.86 ml. of 4- fluoroacetophenone, stirred for3.5 hours, diluted with 0.5 liter of saturated sodium chloride solution,and acidified with acetic acid. The solid was removed by filtration,washed with water and with pentane, dried and digested with 400 ml. ofboiling tetrahydrofuran. Insol- I uble inorganic material which formedwas removed by filtration, and the filtrate was evaporated to dryness.The residue was crystallized from methanol-ether to give 2.1 g. of3-(4-acetylphenoxyimino cyclohexanecarboxylic acid as light browncrystals, m.p. l67l68.5 dec. A solution of 1.9 g. of this material in 25ml. of acetic acid saturated with hydrogen chloride was heated on asteambath for hours. The reaction mixture was cooled to about 25, andthe solid which formed was removed by filtration. Crystallization fromtetrahydrofuran-ether gave 522 mg. of 8- acetyl-l ,2-dihydro-3(4l-1)-dibenzofurancarboxylic acid as grayish crystals, m.p. 234-235.Recrystallized from tetrahydrofuran-ether as white crystals,8-acetyl-1,2- dihydro-3(4H)-dibenzofurancarboxylic acid had a meltingpoint of 234-235. Analysis Calcd. for C H Q, (258.28)

Found: C, 69.72; H, 5.61

Example 28 g.) was distilled to give 55 g. of 3-(4-chloro--phenylthio)-4-oxo-cyclohexanecarboxylic acid ethyl ester as a lightyellow oil, b.p. 190/0.04 mm. The product solidified on standing, paleyellow crystals, m.p. 63-72. The mixture of 25 g. of this material and375 g. of polyphosphoric acid was stirred at 8085 for 3 hours,decomposed with ice and water, and extracted with ether. The ethersolution was washed successively with saturated sodium bicarbonatesolution and water, dried with sodium sulfate, and evaporated to give 23g. of 8-chloro-l ,2,3,4-tetrahydrodibenzothiophene-3- carboxylic acidethyl ester, yellow oil which gradually crystallized, m.p. 60-66. Thismaterial may be used in the next-step without further purification.Recrystallized from hexane as white crystals, 8-chloro-l,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid ethyl ester had a meltingpoint of 75-77. Analysis Calcd. for C, H ClO S (294.80)

Found: C, 61.14; H, 5.13

Example 29 Preparation of 8-chloro-l ,2,3 ,4-

tetrahydrodibenzothiophene-3-carboxylic acid A solution of 22.8 g. of8-chloro-1,2,3,4- tetrahydrodibenzothiophene-3-carboxylic acid ethylester, 320 ml. of 1N sodium hydroxide, and 640 ml. of ethanol werestirred at reflux temperature for 5 hours and then concentrated to asmall volume. The residue was mixed with 0.5 liter of water, charcoal,and thereafter filtered. The filtrate was cooled while adding 50 ml. ofconcentrated hydrochloric acid. The resultant precipitate was removed byfiltration and dried to give 19.1 g. of a solid, m.p. 222-229.Crystallization from acetone-ether gave 10.75 g. of 8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid as yellow crystals, m.p.228-231.

Analysis Calcd. for C H CIO S (266.74)

C, 58.54; H, 4.16 Found: C, 58.65; H, 4.31

Example 30 Preparation of l,2-dihydro-3(4H),8-dibenzofurandicarboxylicacid diethyl ester A solution of 226 mg. of l,2-dihydro-3(4H),8-dibenzofurandicarboxylic acid in 50 ml. of ethanol saturated withhydrogen chloride was heated at reflux temperature for 1 hour whilecontinuing introduction of hydrogen chloride. Gas introduction wasterminated, and the solution was boiled for an additional 2 hours andthen evaporated. The oily residue was dissolved in ml. of methylenechloride and the solution was washed with one 25 ml. portion of 1Nsodium hydroxide and two 25 ml. portions of water. The aqueous layerswere extracted with two 50 ml. portions of methylene chloride. Theorganic layers were combined, dried with anhydrous sodium sulfate andevaporated to dryness to give 247 mg. of oil which crystallized, m.p.5861. Recrystallization from ether-pentane afforded 179 mg. of 1,2-dihydro-3(4H), 8-dibenzofurandicarboxylic acid diethyl ester, m.p.63-63.5. Analysis Calcd. for: C I-1 0 (316.34)

Found: C, 68.49; H, 6.54

Example 3 1 Preparation of 7-chloro-1 ,2-dihydro-3(4H)-dibenzofurancarboxylic acid Z-dimethylaminoethyl esterhydrochloride A mixture of 251 ml. of 7-chloro-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid, 304 mg. of anhydrous potassium carbonateand 25 ml. of dimethylformamide was stirred at room temperature for 0.75hour. A solution of 173 mg. of 2-dimethylaminoethyl chloridehydrochloride in 5 ml. of dimethylformamide was then added and themixture was stirred for 16 hours, heated at reflux temperature for 1hour and evaporated. The residue was dissolved in ml. of methylenechloride and washed with three 50 ml. portions of water. The aqueouslayers were extracted with two 100 ml. portions of methylene chloride.The organic layers were combined, dried with anhydrous sodium sulfateand evaporated. A solution of the residual oil in methanol was acidifiedwith methanolic hydrogen chloride and evaporated. Crystallization of theresidue from methyl-.

ene chloride-ether containing a little methanol yielded 174 mg. of7-chloro-1,2-dihydro-3(4H)-dibenzofuran-.

carboxylic acid Z-dimethylaminoethyl ester hydrochloride, m.p.178.5-l8l. Analysis Calcd. for: C H ClNO l-1Cl (358.27) I C, 56.99; H,5.91; N, 3.91

Found: C, 56.74; H, 5.89; N, 3.87

Example 32 Preparation of 2,3-dihydro-7-nitro-1H-cyclopenta[b]benzofuran-l-carboxylic acid and 1,3-dihydro-7-nitro-2H-cyclopenta[blbenzofuran-Z- carboxylic acid A mixtureof 5.5 g. of potassium t-butoxide and 3.5 g. of3-oxyiminocyclopentanecarboxylic acid in 45 ml. of dimethylsulfoxide wastreated with 2.6 ml. of 4- fluoronitrobenzene, stirred at roomtemperature for 1.5 hours, diluted with 475 ml. of saturated sodiumchloride solution and acidified with acetic acid. The

precipitate which formed was removed by filtration, washed successivelywith water and pentane, dried and crystallized fromtetrahydrofuran-ether-pentane to give 811 mg. of yellow crystals, mp.141 .5142.5. 291 mg. of the product so obtained was treated with 3.5 ml.of a saturated solution of hydrogen chloride in acetic acid, and themixture was stirred for 17 hours at room temperature. The solid wasremoved by filtration, washed with acetic acid and dried to give 201 mg.of white crystals, m.p. 203205 (dec. The product was shown by NMRspectra to contain a 7:3 ratio of 2,3-dihydro-7-nitro-1H-cyclopenta[b]benzofuran-l-carboxylic acid andl,3-dihydro-7-nitro-2H-cyclopenta[ b]benzofuran- 2-carboxylic acid.

2,3-Dihydro-7-nitrol H-cyclopenta[b]benzofuranl carboxylic acid or 1,3-dihydro-7-nitro-2l-lcyclopenta[b]benzofuran-Z-carboxylic acid can beconverted to 2,3-dihydro-7-amino-1H-cyclopenta[b]benzofuran-l-carboxylic acid or 1,3-dihydro-7-amino-2H-cyclopenta[b]benzofuran-2- carboxylic acid,respectively, utilizing known procedures, for example, by chemicalreduction, for instance, with iron and hydrochloric acid, or bycatalytic reduction employing a catalyst, such as Raney nickel and thelike.

2,3-Dihydro-7-aminol l-l-cyclopenta[b]benzofuranl-carboxylic acid or1,3-dihydro-7-amino-2H- cyclopenta[b]benzofuran-Z-carboxylic acid can beconverted to2,3-dihydro-7-acylamido-ll-lcyclopenta[b]benzofuran-l-carboxylic acid or1,3- dihydro-7-acylamido-2l-l-cyclopenta[b]benzofuran-2- carboxylicacid, respectively, utilizing known procedures, for example, acylationwith an acylating agent, such as acyl halide or an acyl anhydride.

2,3-Dihydro-7-amino-1H-cyclopenta[b]benzofuranl-carboxylic acid or1,3-dihydro-7-amino-2l-lcyclopenta[b]benzofuran-Z-carboxylic acid can beconverted to 2,3-dihydro-7-mono-loweralkylaminolH-cyclopenta[b]benzofuran-l-carboxylic acid (or 2,-3-dihydro-7-di-lower-alkylamino-1H- cyclopenta[b]benzofuranl -carboxylicacid) or 1 ,3-dihydro-7-mono-loweralkylamino-2l-lcyclopenta[b]benzofuran-2-carboxylic acid (or 1,3-dihydro-7-di-lower-alkylamino-2l-lcyclopenta[b]benzofuran-Z-carboxylicacid), respectively, utilizing known procedures, for example, utilizingan alkylating agent, such as an alkyl-halide.

2,3-Dihydro-7-aminol l-l-cyclopenta[b]benzofuranl-carboxylic acid or1,3-dihydro-7-amino-2l-lcyclopenta[b]benzofuran-Z-carboxylic acid can beconverted to a diazonium salt utilizing known procedures, for example,by reaction with sodium nitrite and a mineral acid, such as hydrohalicacid. The diazonium group can then be replaced by halogen, cyano,hydroxy, lower alkoxy or hydrogen, utilizing known procedures, forexample, by mixing a diazonium salt solution with, for example, acuprous halide, cuprous cyanide, water, an alcohol or a reducing agent,such as hypophosphoric acid, respectively, at room temperature oroccasionally at elevated temperature to obtain the corresponding2,3-dihydro-7-halo-1H- cyclopenta[b]benzofuran-l-carboxylic acid or 1,3-dihydro-7-halo-2H-cyclopenta[b]benzofuran-Z- carboxylic acid,respectively, or the corresponding 2,3-dihydro-lhydroxy-lH-cyclopenta[b]benzofuran-1- carboxylic acid or1,3-dihydro-7-hydroxy-2H- cyclopenta[b]benzofuran-Z-carboxylic acid,respectively, or the corresponding 2,3-dihydro-7-loweralkoxy-lH-cyclopenta[b]benzofuran-1-carboxylic acid or 1,3-dihydro-7-lower alkoxy-2H- cyclopenta[b]benzofuran-Z-carboxylic acid,respectively, or the corresponding 2,3-dihydro-1H-cyclopenta[b]benzofuran-1-carboxylic acid or 1,3-dihydro-2H-cyclopenta[b]benzofuran-Z-carboxylic acid, respectively.

Example 33 Preparation of 3-(4-cyanophenoxyimino)cyclopentanecarboxylicacid A mixture of 5.5 g. of potassium t-butoxide and 3.65 g. of3-oxyiminocyclopentanecarboxylic acid in 40 ml. of dimethylsulfoxide wastreated with 2.96 g. of 4- fluorobenzonitrile, stirred at roomtemperature for 3 hours, diluted with 400 ml. of saturated sodiumchloride solution and acidified with 25 ml. of acetic acid. Theprecipitate which formed was removed by filtration, washed successivelywith water and pentane, dried and crystallized fromtetrahydrofuran-etherpentane to give 2.5 g. of3-(4-cyanophenoxyimino)cyclopentanecarboxylic acid, tan crystals, m.p.160.516l (dec.)

Analysis Calcd. for C H N O (244.24)

C, 63.92; H, 4.95; N, 11.47

Found: C, 63.70; H, 5.02; N, 11.36

Example 34 Preparation of 7-cyano-2,3-dihydro- 1 H-cyclopenta[b]benzofuran-1-carboxylic acid and 7- cyano-l ,3-dihydro-2l-lcyclopenta[ b] benzofuran-Z- carboxylic acid A mixture of1.06 g. of 3-(4- cyanophenoxyimino)cyclopentane-carboxylic acid and 5ml. of a saturated solution of hydrogen chloride in acetic acid wasstirred for 21 hours at room temperature. The solid was removed byfiltration, washed with hexane-acetic acid (2:1) and then with hexaneand dried to give 1.05 g. of a tan powder, m.p. 206208 (dec.). Theproduct was shown by NMR spectra to be a mixture containing anapproximately 1:1 ratio of 7- cyano-2,3-dihydro-1H-cyclopenta[b]benzofuran-1- carboxylic acid and7-cyano-l,3-dihydro-2l-lcyclopenta[b]benzofuran-Z-carboxylic acid.

7-Cyano-2,3-dihydro-lH-cyclopenta[b]benzofuranl-carboxylic acid or7-cyano-l,3-dihydro-2H- cyclopenta[b]benzofuran-Z-carboxylic acid can beconverted to7-carboxy-2,3-dihydro-ll-lcyclopenta[b]benzofuran-1-carboxylic acid or7- carboxy- 1 ,3 -dihydro-2H-cyclopenta[b benzofuran-2- carboxylic acid,respectively, utilizing known procedures, for example, hydrolysis withacid or base in water or alcohol.

7-Cyano-2,3-dihydrol H-cyclopenta[b benzofuranl-carboxylic acid or7-cyano-l,3-dihydro-2H- cyclopenta[b]benzofuran-Z-carboxylic acid can beconverted to the 7-amido-2 ,3-dihydro-1H- cyclopenta[ b]benzofuran- 1-carboxylic acid or 7-amido-1 ,3-dihydro- 2-cyclopenta[b]benzofuran-2-carboxylic acid, respectively, utilizing known procedures, for example,partial hydrolysis, in strong hydrochloric acid or polyphosphoric acid.

7-Cyano-2,3-dihydrol H-cyclopenta[b benzofuranl-carboxylic acid or7-cyano-l,3-dihydro-2l-I- cyclopenta[b]benzofuran-2-carboxylic acid canbe converted to a 7-lower alkanoyl-2,3-dihydro-1H- Capsule FormulationPer Capsule S-Cyano-l ,2-dihydro-3(4H )-dibenzofurancarboxylic acidLactose, U.S.P. Com Starch, U.S.P. Talc, U.S.P.

l25 mg 30 mg Total Weight 210 mg Procedure:

l. 50 Parts of 8-cyano-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid ismixed with 125 parts of lactose and 30 parts of corn starch in asuitable mixer.

'2. The mixture is further blended by passing through a FitzpatrickComminuting Machine with a No. 1A

- screen with knives forward.

3. The blended powder is returned to the mixer, 5 parts talc are addedand blended'thoroughly.

4. The mixture is filled into No. 4 hard shell gelatin capsules on aParke Davis capsulating machine.

Example 36 Tablet Formulation Per Tablet 8-Cyanol,2-dihydro-3(4l-l)-dibenzofurancarboxylic acid Dicalcium PhosphateDihydrate, Unmilled Corn Starch Magnesium Stearate 25 mg 175 mg 24 mgTotal Weight 225 mg Procedure:

1. 25 Parts of 8-cyano-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid and24 parts of corn starch are mixed together and passed through a No. 00screen in Model J Fitzmill with hammers forward.

2. This premix is then mixed with 175 parts of dicalcium phosphate andone-half of a part of the magnesium stearate, and passed through a No.1A screen in Model J Fitzmill with knives forward, and slugged.

3. The slugs are passed through a No. 2A plate in a Model D Fitzmill atslow speed with knives forward, and the other one-half of a partmagnesium stearate is added.

4. The mixture is mixed and compressed.

Example 37 Tablet Formulation Per Tablet 8-Cyanol ,2-dihydro-3(4H)-dibenzofurancarboxylic acid Lactose, U.S.P.

Corn Starch, U.S.P.

Amijel B011" Calcium Stearate 100 mg 202 mg 80 mg mg 8 mg Total Weight410 mg A prehydrclyzed food grade corn starch. Any similar prehydrolyzedcom starch may be used.

of corn starch, and 20 parts Amijel B0" are blended in a suitable mixer.

2. The mixture is granulated to a heavy paste with water and the moistmass is passed through a No. 12 screen. It is then dried overnight at110F.

3. The dried granules are passed through a No. 16 screen and transferredto a suitable mixer. The calcium stearate is added and mixed untiluniform.

4. The mixture is compressed at a tablet weight of 410 mg using tabletpunches having a diameter of approximately 3/8 inch. (Tablets may beeither flat or biconvex and may be scored if desired.)

Example 38 Parenteral Formulation Procedure (For 10,000 cc):

1. In a clean glass or glass-lined vessel, 8,000 cc of Water forInjection are heated to C. It is then cooled to 5060C, and 18 grams ofmethyl paraben and 2 grams of propyl paraben are added and dissolvedwith stirring. The solution is then allowed to cool to room temperature.

2. The 102.0 grams of 8-cyano-1,2-dihydro-3(4H)- dibenzofurancarboxylicacid is added under an atmosphere of nitrogen and stirred untilcompletely dispersed.

3. The Sodium Hydroxide was added as a 10 percent solution until the pHwas adjusted to 9.0 plus or minur 0.1, and the drug is completelydissolved. I

4. Sufficient Water of Injection is then added to make a total volume of10,000 cc. 7 5. This solution is then filtered through an 02 Selascandle, filled into suitable size ampuls, gassed with nitrogen andsealed. It is autoclaved at 10 lbs PS1 for 30 minutes.

E. F. Drew Company, 522 Fifth Avenue, New York, New York Procedure:

1. 123 Parts of Wecobee M and 4.5 parts of camauba wax are melted in asuitable size glass-lined container (stainless steel may also be used),mixed well and cooled to 45C.

2. 2.5 Parts of 8-cyano-1,'2-dihydro-3(4H)-dibenzofurancarboxylic acid,which has been reduced to a fine powder with no lumps, is added andstirred until completely and uniformly dispersed.

3. The mixture is poured into suppository molds to yield suppositorieshaving an individual weight of 1.3 gms.

4. The suppositories are cooled and removed from molds, and individuallywrapped in wax paper for packaging. (Foil may also be used.)

We claim: 1. A compound of the formula

1. A COMPOUND OF THE FORMULA
 2. A compound in accordance with claim 1,3-(4-nitrophenoxyimino)cyclohexanecarboxylic acid.
 3. A compound inaccordance with claim 1, 2-(4-nitrophenoxyimino)cyclopentanecarboxylicacid.